ABSTRACT Tobacco addiction is a costly and often fatal problem. Even with counseling and nicotine replacement therapy, most smokers relapse following a quit attempt. For many smokers and ex-smokers, cigarette smoking is provoked by affective distress, which includes cigarette cravings. The ability to cope with this distress and remain abstinent depends on one's level of distress tolerance, which is the ability to persist in a goal-directed activity while experiencing physical or affective discomfort. However, a gap in knowledge exists regarding the neural mechanisms that underlie distress tolerance. Identifying these neural mechanisms and understanding individual differences in distress tolerance holds promise for the development of new therapies and the improvement of cessation success through personalized interventions. Past research has shown that cigarette cravings and other forms of affective distress activate the insula, which may be the neural hub that connects the awareness of affective distress to motor and cognitive control regions that determine the subsequent behavioral response (e.g., smoking a cigarette to relieve cravings). However, previous studies that measured functional activity within brain regions have not provided specific information about functional connectivity between the insula and other brain regions. This information is vital to understanding complex behaviors. Based on our preliminary data, our central hypothesis is that insula-based connectivity underlies distress tolerance behavior in relation to smoking cessation. To investigate this hypothesis, we will investigate three Aims: Aim 1) examine the relationship between distress tolerance and insula-based connectivity, Aim 2) identify differences between smokers and ex- smokers, Aim 3) explore brain correlates of distress tolerance using multimodal fusion analysis. This data- driven approach will complement our hypotheses regarding insula-based connectivity. To our knowledge, this is the first study to investigate the neural mechanisms of distress tolerance in the service of smoking cessation. Furthermore, this study will greatly increase our understanding of why some smokers succeed in quitting. This measure could be used in the future to identify and treat smokers at increased risk for distress-related relapse. Thus, successful completion of this study will inform the development of personalized smoking interventions, as well as identify neural mechanisms that can be targeted by novel therapeutic techniques.